Methods and compositions for the treatment of gastrointestinal disorders

• US 20050020811A1
• Filed: 03/09/2004
• Published: 01/27/2005
• Est. Priority Date: 01/28/2003
• Status: Active Grant

• Current Assignee: Ironwood Pharmaceuticals, Inc.
• Original Assignee: Ironwood Pharmaceuticals, Inc.
• Inventors: Currie, Mark G., Mahajan-Miklos, Shalina
• Granted Patent: US 7,304,036 B2
• Time in Patent Office: Days
• US Class Current: 530/327
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/245 Escherichia (G)
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The present invention features compositions and related methods for treating IBS and other gastrointestinal disorders and conditions (e.g., gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn'"'"'s disease, ulcerative colitis, Inflammatory bowel disease, functional heartburn, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastroparesis, chronic intestinal pseudo-obstruction (or colonic pseudo-obstruction), and disorders and conditions associated with constipation, e.g., constipation associated with use of opiate pain killers, post-surgical constipation (post-operative ileus), and constipation associated with neuropathic disorders as well as other conditions and disorders using peptides and other agents that activate the guanylate cyclase C (GC-C) receptor.

Claims

1. A purified peptide comprising the amino acid sequence (I):

Xaa₁ Xaa₂ Xaa₃ Xaa₄ Xaa₅ Cys₆ Cys₇ Xaa₈ Xaa₉ Cys₁₀ Cys₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Cys₁₅ Xaa₁₆ Xaa17 Cys₁₈ Xaa₁₉ Xaa₂₀ Xaa₂₁ (SEQ ID NO;

119) wherein;

Xaa₁ Xaa₂ Xaa₃ Xaa₄ Xaa₅ is Asn Ser Ser Asn Tyr (SEQ ID NO;

121) or is missing or Xaa₁ Xaa₂ Xaa₃ Xaa₄ is missing.

2. The purified peptide of claim 1 wherein Xaa₅ is Asn, Trp, Tyr, Asp, or Phe.

3. The purified peptide of claim 1 wherein Xaa₅ is Thr or Ile.

4. The purified peptide of claim 1 wherein Xaa₅ is Tyr, Asp or Trp.

5. The purified peptide of claim 1 wherein Xaa₈ is Glu, Asp, Gln, Gly or Pro.

6. The purified peptide of claim 1 wherein Xaa₉ is Leu, Ile, Val, Ala, Lys, Arg, Trp, Tyr or Phe.

7. The purified peptide of claim 1 wherein Xaa₉ is Leu, Ile, Val, Lys, Arg, Trp, Tyr or Phe.

8. The purified peptide of claim 1 wherein Xaa₁₂ is Asn, Tyr, Asp or Ala.

9. The purified peptide of claim 1 wherein Xaa₁₃ is Ala, Pro or Gly.

10. The purified peptide of claim 1 wherein Xaa₁₄ is Ala, Leu, Ser, Gly, Val, Glu, Gln, Ile, Leu, Lys, Arg, or Asp.

11. The purified peptide of claim 1 wherein Xaa₁₆ is Thr, Ala, Asn, Lys, Arg, Trp.

12. The purified peptide of claim 1 wherein Xaa₁₇ is Gly, Pro or Ala.

13. The purified peptide of claim 1 wherein Xaa₁₉ is Trp, Tyr, Phe, Asn or Leu.

14. The purified peptide of claim 1 wherein Xaa₁₉ is Lys or Arg.

15. The purified peptide of claim 1 wherein Xaa₂₀ Xaa₂₁ is AspPhe or Xaa₂₀ is Asn or Glu and Xaa₂₁ is missing.

16. The purified peptide of claim 1 wherein Xaa₁₉Xaa₂₀ Xaa₂₁ is missing.

26. A method for treating a gastrointestinal disorder in a patient comprising administering the peptide of claim 1.

29. A method for treating a gastrointestinal disorder in a patient comprising administering the peptide of any of the claims 1, 17-20 and 25, a pharmaceutical acceptable carrier and a second therapeutic agent selected from the group consisting of acid reducing agents including proton pump inhibitors and H2 receptor blockers promotility agents including 5HT receptor agonists and motilin agonists, anti-inflammatory agents, antispasmodics, antidepressants and laxatives and analgesic agents.

32. A method for treating obesity comprising administering the peptide of any of claims 1, 17-20 and 25.

33. A method for treating congestive heart failure comprising administering the peptide of any of claims 1, 17-20 and 25.

34. A method for treating benign prostatic hyperplasia comprising administering the peptide of any of claims 1, 17-20 and 25.

35. The purified peptide of any of claims 1, 17, 18 and 25 wherein the polypeptide comprises the amino acid sequence DF;

QHNPR (SEQ ID NO;

111);

VQHNPR (SEQ ID NO;

112);

VRQHNPR (SEQ ID NO;

113);

VRGQHNPR (SEQ ID NO;

114);

VRGPQHNPR (SEQ ID NO;

115);

VRGPRQHNPR (SEQ ID NO;

116);

VRGPRRQHNPR (SEQ ID NO;

     117);

or RQHNPR (SEQ ID NO;

118) fused to its amino terminus or its caboxy terminus.

36. The purified peptide of any of claims 1, 17, 18 and 25 wherein the purified polypeptide comprises the amino acid sequence of an analgesic peptide selected from the group consisting of endomorphin-1, endomorphin-2, nocistatin, dalargin, lupron, and substance P fused to its amino terminus or its carboxy terminus.

37. The purified peptide of any of claims 1, 17, 18 and 25 wherein the polypeptide includes no more than 10 additional amino acids at its amino terminus or carboxy terminus or both and wherein the polypeptide is a guanylate cyclase receptor agonist.

38. The purified peptide of claim 1 wherein wherein:

Xaa₁ Xaa₂ Xaa₃ Xaa₄ Xaa₅ is missing;

Xaa₈ is Glu;

Xaa₉ is Leu, Ile, Lys, Arg, Trp, Tyr or Phe;

Xaa₁₂ is Asn;

Xaa₁₃ is Pro;

Xaa₁₄ is Ala;

Xaa₁₆ is Thr, Ala, Lys, Arg, Trp;

Xaa₁₇ is Gly;

Xaa₁₉ is Tyr or Leu; and

Xaa₂₀ Xaa₂₁ is AspPhe or is missing.

39. A method for treating a patient suffering from constipation, the method comprising administering the polypeptide of any of claims 1, 17-20 and 25.

40. A method for increasing the activity of an intestinal guanylate cyclase (GC-C) receptor in a patient, the method comprising administering the polypeptide of any of claims 1, 17-20 and 25.

41. A method for increasing intestinal levels of cGMP in a patient, the method comprising administering the polypeptide of any of claims 1, 17-20 and 25.

42. The method of claim 41 wherein the levels of cGMP are increased in intestinal mucosa.

55. A method for treating visceral pain comprising administering the polypeptide of any of claims 1, 17-20 and 25.

56. A method for treating inflammation comprising administering the polypeptide of any of claims 1, 17-20 and 25.

57. A method for treating cystic fibrosis comprising administering the polypeptide of any of claims 1, 17-20 and 25.

59. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25 and a pharmaceutically acceptable carrier.

60. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25 surrounded by an enteric coating.

61. A controlled release pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25 and a biodegradable polymeric matrix.

62. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25, a pharmaceutically acceptable carrier and at least one analgesic agent selected from the group consisting of:

Ca channel blockers (e.g., ziconotide), 5HT receptor agonists, 5HT receptor antagonists, opioid receptor agonists NK1 receptor antagonists, CCK receptor agonists, NK1 receptor antagonists, NK3 receptor antagonists, norepinephrine-serotonin reuptake inhibitors vanilloid and cannabanoid receptor agonists, sialorphin, sialorphin-related peptides

63. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25, a phosphodiesterase inhibitor and a pharmaceutically acceptable carrier.

64. A method for treating cancer, a respiratory disorder, a neurological disorder, a disorder associated with fluid and sodium retention, a disorder associated with carbonate imbalance, erectile dysfunction, an insulin-related disorder, or an inner ear disorder, the method comprising administering the peptide of any of claims 1, 17-20 and 25.

66. A method of producing the peptide of any of claims 1, 17-20 and 25, comprising providing a cell harboring a nucleic acid molecule encoding the polypeptide, culturing the cell under conditions in which the peptide is expressed, and isolating the expressed peptide.

67. A method of producing the peptide of any of claims 1, 17-20 and 25, comprising chemically synthesizing the peptide and they purifying the synthesized peptide.

68. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25 and a natriuretic peptide such as atrial natriuretic peptide, brain natriuretic peptide, a C-type natriuretic peptide, a diuretic, or an inhibitor of angiotensin converting enzyme.

69. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25 and a 5-alpha reductase inhibitor or an alpha adrenergic inhibitor.

70. A pharmaceutical composition comprising the peptide of any of claims 1, 17-20 and 25 and gut hormone fragment peptide YY3-36, glp-1, exendin-4, sibutramine, phentermine, phendimetrazine, benzphetamine hydrochloride, orlistat, diethylpropion hydrochloride, fluoxetine, bupropion, ephedra, chromium, garcinia cambogia, benzocaine, bladderwrack, chitosan, nomame herba, galega, conjugated linoleic acid, L-carnitine, fiber, caffeine, dehydroepiandrosterone, germander, B-hydroxy-β

-methylbutyrate, or pyruvate.

74. A method for treating congestive heart failure comprising administering the peptide of any of claims 1, 17-20 and 25 and a natriuretic peptide such as atrial natriuretic peptide, brain natriuretic peptide, a C-type natriuretic peptide, a diuretic, or an inhibitor of angiotensin converting enzyme.

75. A method for treating benign prostatic hyperplasia comprising administering the peptide of any of claims 1, 17-20 and 25 and a 5-alpha reductase inhibitor or an alpha adrenergic inhibitor.

76. A method for treating obesity comprising administering the peptide of any of claims 1, 17-20 and 25 and gut hormone fragment peptide YY3-36, glp-1 exendin-4, sibutramine, phentermine, phendimetrazine, benzphetamine hydrochloride, orlistat, diethylpropion hydrochloride, fluoxetine, bupropion, ephedra, chromium, garcinia cambogia, benzocaine, bladderwrack, chitosan, nomame herba, galega, conjugated linoleic acid, L-camitine, fiber, caffeine, dehydroepiandrosterone, germander, B-hydroxy-β

-methylbutyrate, or pyruvate.

17. A purified peptide comprising the amino acid sequence:

18. A purified peptide comprising the amino acid sequence:

19. A purified peptide consisting of the amino acid sequence:

20. A purified peptide consisting of the amino acid sequence:

21. A method for treating a gastrointestinal disorder in a patient comprising administering a purified peptide comprising the amino acid sequence:

Asn Ser Ser

30. The method of any of claims 21-24, 26, 27 and 28 wherein the gastrointestinal disorder is a gastrointestinal motility disorder.

31. The method of any of claims 21-24, 26, 27 and 28 wherein the gastrointestinal disorder is selected from the group consisting of a gastrointestinal motility disorder, irritable bowel syndrome, chronic constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn'"'"'s disease, ulcerative colitis, inflammatory bowel disease and post-operative ileus.

22. A method for treating a gastrointestinal disorder in a patient comprising administering a purified peptide comprising the amino acid sequence:

23. A method for treating a gastrointestinal disorder in a patient comprising administering a purified peptide comprising the amino acid sequence:

24. A method for treating a gastrointestinal disorder in a patient comprising administering a purified peptide comprising the amino acid sequence:

25. A purified polypeptide comprising an amino acid sequence of any of:

27. A method for treating a gastrointestinal disorder in a patient comprising administering the peptide of claim 25.

28. A method for treating a gastrointestinal disorder in a patient comprising administering a GC-C receptor agonist, a pharmaceutical acceptable carrier and a second therapeutic agent selected from the group consisting of acid reducing agents including proton pump inhibitors and H2 receptor blockers promotility agents including 5HT receptor agonists and motilin agonists, anti-inflammatory agents, antispasmodics, antidepressants and laxatives and analgesic agents.

43. A method for increasing intestinal levels of cGMP in a patient, the method comprising administering a GC-C receptor agonist.

44. The method of claim 43 wherein levels of cGMP are increased in intestinal mucosa.

45. A method for increasing the activity of an intestinal guanylate cyclase (GC-C) receptor in a patient, the method comprising administering a GC-C receptor agonist.

46. A method for treating a gastrointestinal disorder in a patient comprising administering a GC-C receptor agonist.

47. The method of claim 46 wherein the gastrointestinal disorder is a gastrointestinal motility disorder.

48. The method of claim 46 wherein the gastrointestinal disorder is selected from the group consisting of a gastrointestinal motility disorder, irritable bowel syndrome, chronic constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn'"'"'s disease, ulcerative colitis inflammatory bowel disease and post-operative ileus.

49. A method for treating obesity comprising administering a GC-C receptor agonist.

50. A method for treating congestive heart failure comprising administering a GC-C receptor agonist.

51. A method for treating benign prostatic hyperplasia comprising administering a GC-C receptor agonist.

52. A method for treating visceral pain comprising administering a GC-C receptor agonist.

53. A method for treating inflammation comprising administering a GC-C receptor agonist.

54. A method for treating constipation comprising administering a GC-C receptor agonist.

58. A method for treating cystic fibrosis comprising administering a GC-C receptor agonist.

65. A method for treating cancer, a respiratory disorder, a neurological disorder, a disorder associated with fluid and sodium retention, a disorder associated with carbonate imbalance, erectile dysfunction, an insulin-related disorder, or an inner ear disorder, the method comprising administering a GC-C receptor agonist.

71. A pharmaceutical composition comprising a GC-C receptor agonist and a natriuretic peptide such as atrial natriuretic peptide, brain natriuretic peptide, a C-type natriuretic peptide, a diuretic, or an inhibitor of angiotensin converting enzyme.

72. A pharmaceutical composition comprising a GC-C receptor agonist and a 5-alpha reductase inhibitor or an alpha adrenergic inhibitor.

73. A pharmaceutical composition comprising a GC-C receptor agonist and gut hormone fragment peptide YY3-36, glp-1, exendin-4, sibutramine, phentermine, phendimetrazine, benzphetamine hydrochloride, orlistat, diethylpropion hydrochloride, fluoxetine, bupropion, ephedra, chromium, garcinia cambogia, benzocaine, bladderwrack, chitosan, nomame herba, galega, conjugated linoleic acid, L-carmitine, fiber, caffeine, dehydroepiandrosterone, germander, B-hydroxy-β

-methylbutyrate, or pyruvate.

77. A method for treating congestive heart failure comprising administering a GC-C receptor agonist and a natriuretic peptide such as atrial natriuretic peptide, brain natriuretic peptide, a C-type natriuretic peptide, a diuretic, or an inhibitor of angiotensin converting enzyme.

78. A method for treating benign prostatic hyperplasia comprising a GC-C receptor agonist and a 5-alpha reductase inhibitor or an alpha adrenergic inhibitor.

79. A method for treating obesity comprising administering a GC-C receptor agonist and gut hormone fragment peptide YY3-36, glp-1, exendin-4, sibutramine, phentermine, phendimetrazine, benzphetamine hydrochloride, orlistat, diethylpropion hydrochloride, fluoxetine, bupropion, ephedra, chromium, garcinia cambogia, benzocaine, bladderwrack chitosan, nomame herba, galega, conjugated linoleic acid, L-carnitine, fiber, caffeine, dehydroepiandrosterone, germander, B-hydroxy-β

-methylbutyrate, or pyruvate.